Glycogen storage disease (GSD) type 1 is an autosomal recessive disease caused by the deficiency of glucose-6-phosphatase (G6Pase). Five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), and glucose (1d) translocases. We have characterized the cDNA and gene for G6Pase, analyzed the G6Pase gene of twelve type 1a patients, and uncovered a total of six mutations that cause GSD type 1a. We have also characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP patients. Our results show that the G6Pase gene of GSD type 1b and 1c patients is normal. However, an R83C mutation found in several GSD type 1a patients was identified in both G6Pase alleles of the type 1aSP patient, indicating that type 1aSP is a misclassification of GSD type 1a. Hepatic S-adenosylmethionine (AdoMet) synthetase catalyzes the biosynthesis of AdoMet which functions in transmethylation and transsulfuration. Deficiency of hepatic AdoMet synthetase causes persistent hypermethioninemia and unusual breath odor. To understand the molecular basis of this disorder, we characterized the cDNA and gene for human hepatic AdoMet synthetase. Using SSCP and DNA sequencing analyses, we identified four mutations in the AdoMet synthetase gene of two compound heterozygous patients. To understand the molecular mechanisms underlying differential PSG expression, we characterized promoter elements of six PSG genes. Nucleotides -172 to -34 with respect to the translation start site constitute a minimal promoter in class 1 PSG genes and only nucleotides - 172 to -80 are necessary for promoter activity in class 2 PSG genes. Class 2 genes contain a perfect Sp1 recognition sequence which is necessary for promoter activity and binds to an Sp1-like molecule in placental extracts. Moreover, an activator sequences is located within nucleotides -83 to -34 in PSG12 (a class 1 gene) which binds to a 50 kDa protein share immunological reactivity with the transcription factor PEA3. We have demonstrated that the 5'-flanking region of a rat PSG gene, rnCGM3, contains two promoter elements (PI and PII) located upstream and downstream of the transcription start site, respectively. The PISII site within the PI promoter binds to C/EBP- in placental extracts and transactivates rnCGM3 expression. C/EBP-, a leucine zipper family of transcription factor, is expressed in high levels in the placenta and constitutes one of the transcription factors that positively regulate rnCGM3 expression during pregnancy.